differentiation

Stanford and University of Tokyo researchers crack the code for blood stem cells

/ Yimy Villa / 1 Comment
Blood stem cells grown in lab

Blood stem cells offer promise for a variety of immune and blood related disorders such as sickle cell disease and leukemia. Like other stem cells, blood stem cells have the ability to generate additional blood stem cells in a process called self-renewal. Additionally, they are able to generate blood cells in a process called differentiation. These newly generated blood cells have the potential to be utilized for transplantations and gene therapies.

However, two limitations have hindered the progress made in this field. One problem relates to the amount of blood stem cells needed to make a potential transplantation or gene therapy viable. Unfortunately, it has been challenging to isolate and grow blood stem cells in large quantity needed for these approaches. A part of this reason relates to getting the blood stem cells to self-renew rather than differentiate.

The second problem involves the existing blood stem cells in the patient’s body prior to transplantation. In order for the procedure to work, the patient’s own blood stem cells must be eliminated to make space for the transplanted blood stem cells. This is done through a process known as conditioning, which typically involves chemotherapy and/or radiation. Unfortunately, chemotherapy and radiation can cause life-threatening side effects due to its toxicity, particularly in pediatric patients, such as growth retardation, infertility and secondary cancer in later life. Very sick or elderly patients are unable to tolerate this conditioning process, making them ineligible for transplants.

A CIRM funded study by a team at Stanford and the University of Tokyo has unlocked the code related to the generation of blood stem cells.

The collaborative team was able to modify the components used to grow blood stem cells. By making these modifications, which effects the growth and physical conditions of blood stem cells, the researchers have shown for the first time that it’s possible to get blood stem cells from mice to renew themselves hundreds or even thousands of times within a period of just 28 days. 

Furthermore, the team showed that when they transplanted the newly grown cells into mice that had not undergone conditioning, the donor cells had engrafted and remained functional.

The team also found that gene editing technology such as CRISPR could be used while growing an adequate supply of blood stem cells for transplantation. This opens the possibility of obtaining a patient’s own blood stem cells, correcting the problematic gene, and reintroducing these back to the patient.

The complete study was published in Nature.

In a news release, Dr. Hiromitsu Nakauchi, a senior author of the study, is quoted as saying,

“For 50 years, researchers from laboratories around the world have been seeking ways to grow these cells to large numbers. Now we’ve identified a set of conditions that allows these cells to expand in number as much as 900-fold in just one month. We believe this approach could transform how [blood] stem cell transplants and gene therapy are performed in humans.” 

Stories that caught our eye: color me stem cells, delivering cell therapy with nanomagnets, and stem cell decisions

/ Todd Dubnicoff / Leave a comment

Nanomagnets: the future of targeted stem cell therapies? Your blood vessels are made up of tightly-packed endothelial cells. This barrier poses some big challenges for the delivery of drugs via the blood. While small molecules are able make their way through the small gaps in the blood vessel walls, larger drug molecules, including proteins and cells, are not able to penetrate the vessel to get therapies to diseased areas.

This week, researchers at Rice University report in Nature Communications on an ingenious technique using tiny magnets that may overcome this drug delivery problem.

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At left, the nanoparticles are evenly distributed among the microtubules that help give the cells their shape. At right, after a magnetic field is applied, the nanoparticles are pulled toward one end of the cells and change their shapes. Credit: Laboratory of Biomolecular Engineering and Nanomedicine/Rice University

Initial studies showed that adding magnetic nanoparticles to the endothelial cells and then applying a magnetic field affected the cells’ internal scaffolding, called microtubules. These structures are responsible for maintaining the tight cell to cell connections. The team took the studies a step further by growing the cells in specialized petri dishes containing tiny, tube-shaped channels. Applying a magnetic field to the cells caused the cell-cell junctions to form gaps, making the blood vessel structures leaky. Simply turning off the magnetic field closed up the gaps within a few hours.

Though a lot of research remains, the team aims to apply this on-demand induction of cell leakiness along with adding the magnetic nanoparticles to stem cell therapy products to help target the treatment to specific area. In a press release, team leader Dr. Gang Bao spoke about possible applications to arthritis therapy:

“The problem is how to accumulate therapeutic stem cells around the knee and keep them there. After injecting the nanoparticle-infused cells, we want to put an array of magnets around the knee to attract them.”

To differentiate or not differentiate: new insights During the body’s development, stem cells must differentiate, or specialize, into functional cells – like liver, heart, brain. But once that specialization occurs, the cells lose their pluripotency, or the ability to become any type of cell. So, stem cells must balance the need to differentiate with the need to make copies of itself to maintain an adequate supply of stem cells to complete the development process. And even after a fully formed baby is born, it’s still critical for adult stem cells to balance the need to regenerate damaged tissue versus stashing away a pool of stem cells in various organs for future regeneration and replacement of damaged or diseased tissues.

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Visualizing activation of Nanog gene activity (bright green spot) within cell nucleus. 
Image: Courtesy of Bony De Kumar, Ph.D., and Robb Krumlauf, Ph.D., Stowers Institute for Medical Research

A report this week in the Proceedings of the National Academy of Sciences finds evidence that the two separate processes – differentiation and pluripotency – directly communicate with each other as way to ensure a proper balance between the two states.

The study, carried out by researchers at Stowers Institute for Medical Research in Kansas City, Missouri, focused on the regulation of two genes: Nanog and Hox. Nanog is critical for maintaining a stem cell’s ability to become a specialized cell type. In fact, it’s one of the four genes initially used to reprogram adult cells back into induced pluripotent stem cells. The Hox gene family is responsible for generating a blueprint of the body plan in a developing embryo. Basically, the pattern of Hox gene activity helps generate the body plan, basically predetermining where the various body parts and organs will form.

Now, both Nanog and Hox proteins act by binding to DNA and turning on a cascade of other genes that ultimately maintain pluripotency or promote differentiation. By examining these other genes, the researchers were surprised to find that both Nanog and Hox were bound to both the pluripotency and differentiation genes. They also found that Nanog and Hox can directly inhibit each other. Taken together, these results suggest that exquisite control of both processes occurs cross regulation of gene activity.

Dr. Robb Krumlauf one of authors on the paper talked about the significance of the result in a press release:

“Over the past 10 to 20 years, biologists have shown that cells are actively assessing their environment, and that they have many fates they can choose. The regulatory loops we’ve found show how the dynamic nature of cells is being maintained.”

Color me stem cells Looking to improve your life and the life of those around you? Then we highly recommend you pay a visit to today’s issue of Right Turn, a regular Friday feature of  Signals, the official blog of CCRM, Canada’s public-private consortium supporting the development of regenerative medicine technologies.

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Collage sample of CCRM’s new coloring sheets. Image: copyright CCRM 2017

As part of an public outreach effort they have created four new coloring sheets that depict stem cells among other sciency topics. They’ve set up a DropBox link to download the pictures so you can get started right away.

Adult coloring has swept the nation as the hippest new pastime. And it’s not just a frivolous activity, as coloring has been shown to have many healthy benefits like reducing stressed and increasing creativity. Just watch any kid who colors. In fact, share these sheet with them, it’s intended for children too.

The key to unlocking stem cell’s potential and blocking a deadly threat

/ Kevin McCormack / Leave a comment

A small slice of who you are - brain cells made from embryonic stem cells.

A small slice of who you are – brain cells made from embryonic stem cells.

Our bodies are amazingly complex systems. By some estimates there are more than 37 trillion cells in our bodies.  That’s trillion with a “t”. Each of those cells engages in some form of communication and signaling with other cells which makes our bodies one heck of a busy place to be.

Yet all this activity may owe much of its splendor and complexity to a relatively small number of starting materials. Key among those may be one protein which seems to act like a “master switch” and can determine if a cell changes and multiplies, or just stays the same.

Starting out

But let’s begin at the beginning. We all start out as a single fertilized egg that develops into embryonic stem cells, which in turn become adult stem cells, which then give rise to all the different cells and tissues and structures in our body – such as our bones and brains and blood.

But how do those cells know when to change, what to change into, and when to stop? Change too little and something is undeveloped. Change too much and you risk the kind of explosive uncontrolled multiplication of cells that you see in cancer.

So, clearly, knowing what controls those changes in stem cells, and learning how to use it, could have an enormous impact on our ability to use stem cells to treat a wide range of diseases.

What’s in a name, or a number

Now researchers at Mount Sinai have identified a single protein that appears to play a major role in this control process. The protein is called zinc finger protein 217 (ZFP217) and it controls the actions of genes that in turn control whether a cell changes into another kind of cell and how often it keeps dividing and multiplying.

The study is published in Cell Stem Cell  and there is some pretty complex science involved but ultimately what it boils down to is that ZFP217 has an impact on m6A (scientists really need to start coming up with more imaginative names) which is a protein that helps determine if a gene is turned on or off. If turned on the gene performs one function. If turned off it doesn’t.

By, in effect, blocking the action of m6A, ZFP217 is able to stop the process that would allow stem cells to differentiate, or change, into other cells and also ends their ability to keep renewing themselves.

But wait, there’s more!

One other important role that ZFP217 plays is in helping spur the growth of cancerous tumors. Too much of the protein allows these cells to multiply in an unlimited and uncontrolled fashion, typical of the kind of growth we see in tumors.

The study was done in mice but in a news release  the lead study author, Martin Walsh, PhD, talked about the possible significance of the findings for people:

“The hope is that ZFP217 could be used to maintain supplies of therapeutic stem cells. At the same time, as the human ZPF217 is associated with poor survival in a variety of cancers, understanding how this protein operates in physiological conditions may help to predict cancer risk, achieve earlier diagnosis and provide novel therapeutic approaches.”

Having a deeper understanding of what makes some stem cells multiply and change into other cells could enable researchers to better use stem cells to develop new approaches to treating some of the most intractable diseases of our time.

If that happens then ZFP217 might be a name to remember after all.